Tuesday, December 5, 2023
| Regimen | Drug 1, dose | Drug 2, dose |
|---|---|---|
| Levofloxacin/ethambutol | Levofloxacin, ≤5 y: 15–20 mg/kg, >5 y: 7.5–10 mg/kg; max. dose 1,000 mg/d | Ethambutol, 15–25 mg/kg; max. dose 2,000 mg/kg |
| Levofloxacin/ethionamide | Levofloxacin, ≤5 y: 15–20 mg/kg, >5 y: 7.5–10 mg/kg; max. dose 1,000 mg/d | Ethionamide, 15–20 mg/kg; max. dose 750 mg/kg |
| Moxifloxacin/ethambutol | Moxifloxacin, 7.5–10 mg/kg; max. dose 400 mg/d | Ethambutol, 15–25 mg/kg; max. dose 2,000 mg/kg |
| Moxifloxacin/ethionamide | Moxifloxacin, 7.5–10 mg/kg; max. dose 400 mg/d | Ethionamide, 15–20 mg/kg; max. dose 750 mg/kg |
| *Max., maximum. | ||
Table 1. Preventive therapy regimens in study of persons exposed at home to drug-resistant tuberculosis, Karachi, Pakistan, February 2016–March 2017*
| Characteristic | Becerra et al.[25] | Fox et al.[22] | Reichler et al.[26] | Martin-Sanchez et al.[27] | Sloot et al.[28] | Saunders et al.[29] |
|---|---|---|---|---|---|---|
| Setting | Peru | Global | US and Canada | Spain | Netherlands | Peru |
| Year | 2013 | 2013 | 2019 | 2019 | 2014 | 2017 |
| HHC age group, y | ||||||
| <15 | 1,299 | N/A | 879 | 77 | 1,489 | NA |
| ≥15 | 3,411 | N/A | 3,611 | 876 | 7,757 | 1,910 |
| IR or risk | IR and risk | IR and risk | IR and risk | IR and risk | Risk | Risk |
| IR or risk by PT status | No PT for DR TB exposure | No | Yes | Yes | Yes | No |
| IR or risk by age and year of follow-up | Yes | Not by age but by year of follow-up | No | No cases in children | No | No |
| IR or risk by risk group | No | No | Yes | Yes | No | Yes |
| IR or risk reported | <15 y, Y 1: 2,079/100,000 p-y; <15 y, Y 2: 315/100,000 p-y; ≥15 y, Y 1: 2,610/100,000 p-y; ≥15 y, Y 2: 1,309/100,000 p-y; risk: 163/4,515 (3.6%) | Y 1: 1,478/100,000 p-y; Y 2: 831/100,000 p-y; risk: 898/65,935 (1.4%) | Rate: 951/100,000 p-y; 5 y risk for TST-positive contacts without PT: 49/446 (11.0%) | Rate: 1970/100,000 p-y; 5 y risk for TST-positive contacts not completing PT: 6/72 (8.3%) | 2 y risk in TST-positive contacts without PT: 9/372 (2.4%) | 2.5 y risk for medium- to high-risk contacts in validation cohort: 57/1,335 (4.3%) |
| Other limitations | Some children received isoniazid-based PT | NA | P-y accumulated over 5 y | No cases in children less than 15 y; p-y accumulated over 5.3 y | Definition of incidence >6 mo | HHCs >15 y |
Table 2. Details of studies from which data were extracted for analysis in study of persons exposed at home to drug-resistant tuberculosis, Karachi, Pakistan, February 2016–March 2017*
*DR TB, drug-resistant tuberculosis; HHC, household contacts; IR, incidence rate; PT, preventive therapy; p-y, person-years; TST, tuberculin skin test; Y, year of follow-up; NA, data not available.
| Characteristic | No. (%) or median [IQR] | |||
|---|---|---|---|---|
| Total, n = 789† | On PT, n = 172 | Did not start PT, n = 43 | Not eligible for PT, n = 574 | |
| Age group, y | 19 [10–32] | 7 [3–15] | 16 [3–22] | 24 [15–36] |
| <15 | 283 (36) | 128 (74) | 21 (49) | 134 (23) |
| ≥15 | 506 (64) | 44 (26) | 22 (51) | 440 (77) |
| Sex | ||||
| M | 423 (54) | 91 (53) | 20 (47) | 312 (54) |
| F | 366 (46) | 81 (47) | 23 (53) | 262 (46) |
| BMI, kg/m2 | 18.1 [14.8–24.0], n = 616 | 14.8 [13.4–16.9], n = 171 | 15.2 [13.4–16.9], n = 42 | 21.6 [17.1–26.0], n = 403 |
| Presence of symptoms | n = 737 | n = 172 | n = 43 | n = 522 |
| Cough, duration | 10 (1) | 3 (2) | 2 (5) | 5 (1) |
| Fever | 7 (1) | 1 (1) | 3 (7) | 3 (1) |
| Weight loss | 12 (2) | 1 (1) | 2 (5) | 9 (2) |
| Additional TB risk factors | n = 737 | n = 172 | n = 43 | n = 522 |
| History of TB | 9 (1) | 0 (0) | 0 (0) | 9 (2) |
| TST >5 mm | 6/136 (4) | 6/64 (9) | 0/11 (0) | 0/61 (0) |
| Index patient resistant to FQ | 138 (19) | 16 (9) | 11 (26) | 111 (21) |
| Regimen given | ||||
| Levofloxacin/ethambutol | NA | 102 (59) | NA | NA |
| Levofloxacin/ethionamide | NA | 54 (31) | NA | NA |
| Moxifloxacin/ethambutol | NA | 11 (6) | NA | NA |
| Moxifloxacin/ethionamide | NA | 5 (3) | NA | NA |
| TB disease occurred during follow-up | 2 (0.3) | 2 (1) | 0 | 0 |
Table 3. Demographics and clinical characteristics of household contacts exposed to drug-resistant tuberculosis free of disease at baseline in study of preventive therapy in Karachi, Pakistan, February 2016–March 2017*
*FQ, fluoroquinolone; NA, not applicable; PT, preventive therapy; TB, tuberculosis; TST, tuberculin skin test.
†Excluding 3 contacts found to have TB and 8 already on treatment for TB at time of screening.
| Characteristic | Becerra et al.[25] | Fox et al.[22] | Reichler et al.[26] | Martin-Sanchez et al.[27] |
|---|---|---|---|---|
| No. expected cases | 4.7 | 3.9 | 6.6 | 6.6 |
| Expected IR per 1,000 p-y | 15 | 12 | 20 | 20 |
| IRR (95% CI) | 0.40 (0.05–2.0) | 0.50 (0.06–2.8) | 0.29 (0.04–1.3) | 0.29 (0.04–1.3) |
| IR difference per 1,000 p-y (95% CI) | −8.0 (–23.0 to 7.1) | −5.7 (–20.0 to 8.5) | −14 (–31.0 to 3.4) | −14 (–31.0 to 3.4) |
| NNT | 64 | 91 | 37 | 37 |
| Preventive fraction in exposed, % | 57.5 | 48.7 | 69.5 | 69.7 |
Table 4. Incidence rate comparison of effectiveness of preventive therapy for tuberculosis in published studies in study of persons exposed at home to drug-resistant tuberculosis, Karachi, Pakistan*
*IR, incidence rate; IRR, incidence rate ratio; NNT, number needed to treat; p-y, person-years.
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In Karachi, Pakistan, a South Asian megacity with a high prevalence of tuberculosis (TB) and low HIV prevalence, we assessed the effectiveness of fluoroquinolone-based preventive therapy for drug-resistant (DR) TB exposure. During February 2016–March 2017, high-risk household contacts of DR TB patients began a 6-month course of preventive therapy with a fluoroquinolone-based, 2-drug regimen. We assessed effectiveness in this cohort by comparing the rate and risk for TB disease over 2 years to the rates and risks reported in the literature. Of 172 participants, TB occurred in 2 persons over 336 person-years of observation. TB disease incidence rate observed in the cohort was 6.0/1,000 person-years. The incidence rate ratio ranged from 0.29 (95% CI 0.04–1.3) to 0.50 (95% CI 0.06–2.8), with a pooled estimate of 0.35 (95% CI 0.14–0.87). Overall, fluoroquinolone-based preventive therapy for DR TB exposure reduced risk for TB disease by 65%.
Tuberculosis (TB) is the leading infectious cause of death globally and the 9th leading cause overall[1]. TB causes ≈10 million new cases and 1.7 million deaths annually[1]. Annually, ≈650,000 TB patients have multidrug-resistant (MDR) TB, defined as TB that is resistant to both isoniazid and rifampin[1]. Treatment for MDR TB is toxic, complex, and prolonged, and it has a success rate of only 55%[1–3]. Therefore, preventive interventions, including preventive therapy and future vaccines, are essential to reduce cases and deaths from MDR TB[4,5].
Delivering effective treatment for exposure to drug-resistant (DR) TB is central to the work of Zero TB Initiative coalitions, which aim to rapidly drive down TB rates worldwide[6]. Household contacts of persons with DR TB are at high risk for TB[7] and are prime candidates for preventive interventions[8]. Available standard preventive therapies are not expected to protect persons exposed to MDR TB because the infecting TB strain in the exposed person is highly likely to be resistant to isoniazid and rifampin. A meta-analysis of 33 studies found that >80% of household contacts of persons with DR TB in whom TB occurred also had isoniazid-resistant strains[9]. Thus, household contacts of persons with DR TB should receive treatment under the assumption that they, too, are infected with a DR Mycobacterium tuberculosis strain[9].
Evidence is limited regarding effective preventive regimens for MDR TB, in contrast to the abundant evidence available for preventive therapy in isoniazid-sensitive TB[10]. Although data from randomized controlled trials are not available to guide the approach to preventive therapy for MDR TB, observational studies from the Federated States of Micronesia, United States, United Kingdom, and South Africa have shown efficacy of fluoroquinolone-based preventive therapy in adults and children[11–17]. The largest observational study with a comparison arm, from the Federated States of Micronesia, described 104 household contacts of persons with MDR TB who received preventive therapy with a fluoroquinolone-based regimen for 12 months. During 3 years of follow-up, TB did not occur in any of the contacts who received preventive therapy; in 3 (20%) of the 15 contacts who refused treatment, MDR TB occurred. A meta-analysis of observational studies determined MDR TB preventive therapy to be 90% effective, and a wide range of 9%–99% effectiveness was reported[18].
Most studies of preventive therapy for MDR TB have been conducted in either high-resource settings or settings with a high prevalence of HIV. Hence, evaluations of the effectiveness of MDR TB preventive therapy in other settings are needed. In Karachi, Pakistan, which has a high TB burden and low HIV prevalence setting (annual TB incidence of 265/100,000 and HIV prevalence [among persons 15–49 years of age] of 0.1%)[1,19], we examined the effectiveness of fluoroquinolone-based 2-drug preventive therapy for high-risk household contacts of persons with DR TB.
